Pharmaceutical composition

ABSTRACT

A pharmaceutical composition comprising an analgesic or analgesic combination and a stool softener is disclosed. The analgesic is selected from morphine, meperidine, fentanyl, hydromorphone, oxymorphone, oxycodone, hydrocodone, methadone, propoxyphene, pentazocine, levorphanol, codeine, acetaminophen and combinations of these analgesics. The composition is formulated for oral administration as a liquid or solid dosage form for immediate, slow, delayed or sustained-release characteristics.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/426,867 filed Nov. 15, 2002, which is incorporated in itsentirety by this reference.

FIELD OF THE INVENTION

The invention resides in the field of analgesic-based pharmaceuticalcompositions.

BACKGROUND OF THE INVENTION

Oral analgesics and analgesic combinations have become some of the mostfrequently prescribed medications for the treatment of patientsexperiencing both acute and chronic pain. This use has increasedrecently with newer and more progressive pain treatment regimensemphasizing aggressive and preventive approaches to pain management.Unfortunately, many of the available opiate and opiate-relatedanalgesics are constipating. This adverse effect often necessitatesdosage reduction or diet modification to alleviate or preventconstipation in chronic pain patients.

One method of preventing and treating constipation associated with theuse of opiates and their analogs is the administration of laxatives.This measure has the advantage of preventing further complications andside effects caused by medication prescribed to a patient suffering painthat requires pharmaceutical intervention. Stool softening laxatives orbulk laxatives are typically chosen over irritant or stimulatorylaxatives to alleviate constipation in these patients without adverselyaffecting electrolyte imbalance or digestion and absorption of othermedications and foods.

Typically, patients prescribed opiate-containing analgesics on anoutpatient basis are instructed to purchase and use a non-prescriptionstool softening product. In many instances, these patients eitherforget, or choose not to purchase the recommended stool softenerresulting in constipation that is later more difficult to treat than toinitially prevent. Additionally, those patients that do begin use of astool softener do not vary the dose of the laxative as their opiate useincreases or decreases, often resulting in constipation or diarrhea.Thus, there exists a need for a pharmaceutical dosage from incorporatingopiate analgesics and analgesic combinations and a stool softener thatwill inherently increase or reduce the dosage of the laxativeconcurrently with a patient's opiate use.

SUMMARY OF THE INVENTION

The invention is directed to a pharmaceutical composition comprising ananalgesic and a stool softener. The analgesic may be morphine,meperidine, fentanyl, hydromorphone, oxymorphone, oxycodone,hydrocodone, methadone, propoxyphene, pentazocine, levorphanol, codeineor combinations of these analgesics. The stool softener may be anycompound known to increase the water content of the colon and therebysoften the stool. For example, it is known that laxatives traditionallythought of as bulk laxatives will function to soften the stool byincreasing the water content of the stool and these bulk laxatives aretherefore to be included within the term stool softener for the purposesof this disclosure. Preferably, the stool softeners for use in thepharmaceutical compositions of the present invention may be docusate,poloxamer 188, psyllium, methylcellulose, carboxymethyl cellulose,polycarbophil, bisacodyl, castor oil, magnesium citrate, magnesiumhydroxide, magnesium sulfate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium biphosphate or combinations of these compounds.Preferably, the pharmaceutical composition comprises between about 0.10grams to 10.0 grams of psyllium. In further embodiments of theinvention, the pharmaceutical composition comprises between about 0.25grams and about 2 grams, or between about 0.5 grams and about 5 grams ofpsyllium.

In a preferred embodiment of the invention, the pharmaceuticalcomposition further comprises between about 10 mg and about 2000 mg ofacetaminophen. In a more preferred embodiment of the invention, thepharmaceutical composition comprises between about 50 mg and about 1000mg, or between about 325 mg and about 750 mg of acetaminophen.

Preferably, the pharmaceutical compositions of the present invention areformulated as single oral dosage forms such as oral solutions, oralsyrups, soft gelatin capsules, hard gelatin capsules, tablets, capsulesand sterile packaged powder including pharmaceutically-acceptableexcipients. In another embodiment of the present invention, thepharmaceutical composition is formulated in a sustained release carrierthat causes the analgesic, the stool softener or both to be releasedover an extended time period following oral administration to a humanpatient. Preferably, the time period of sustained release of theanalgesic is a period of about 4 to about 16 hours or a period of about8 to about 24 hours after being orally administered to a human patient.In another embodiment of the present invention the pharmaceuticalcomposition comprises codeine and at least about 50 mg of docusate. Thisembodiment may also contain a non-opioid analgesic such as acetaminophenin a range of between about 10 mg to about 2000 mg of acetaminophen. Ina preferred embodiment of the invention, the pharmaceutical compositionfurther comprises between about 10 mg and about 2000 mg ofacetaminophen. In further embodiments of the invention, thepharmaceutical composition can contain between about 50 mg and about1000 mg, or between about 325 mg and about 750 mg of acetaminophen.

The invention also provides a method of preventing constipation duringanalgesic use by co-administering a stool softener with an analgesic ina single oral dosage form. The analgesic used in the method may bemorphine, meperidine, fentanyl, hydromorphone, oxymorphone, oxycodone,hydrocodone, methadone, propoxyphene, pentazocine, levorphanol, codeine,acetaminophen or combinations of these analgesics and the stool softenermay be docusate, poloxamer 188, psyllium, methylcellulose, carboxymethylcellulose, polycarbophil, bisacodyl, castor oil, magnesium citrate,magnesium hydroxide, magnesium sulfate, dibasic sodium phosphate,monobasic sodium phosphate, sodium biphosphate or combinations of thesecompounds.

In one preferred embodiment, the pharmaceutical composition comprisesbetween about 10 mg to about 300 mg of docusate. In further embodimentsof the invention, the pharmaceutical composition comprises between about25 mg and about 200 mg, or between about 50 mg and about 100 mg ofdocusate.

In another preferred embodiment, the pharmaceutical compositioncomprises between about 0.10 grams to about 10.0 grams of psyllium. Infurther embodiments of the invention, the pharmaceutical compositioncomprises between about 0.25 grams and about 2 grams, or between about0.5 grams and about 5 grams of psyllium.

In yet another embodiment, the pharmaceutical composition includes oneor more pharmaceutically acceptable inert excipients. In a preferredembodiment, the single oral dosage form used in the method also containsacetaminophen, and in another embodiment, the dosage form containingthese medications is formulated in a sustained release carrier allowingthe analgesics or stool softeners to be released over an extended timeperiod when orally administered to a human patient. Preferably, the timeperiod of sustained release of the analgesic is a period of about 8 toabout 24 hours after being orally administered to a human patient.

Another embodiment of the present invention is a method of preventingconstipation during analgesic use by the administration of a single oraldosage form comprising codeine and at least about 50 mg of docusate. Ina preferred embodiment, the oral dosage form also contains a non-opioidanalgesic such as acetaminophen, and may be formulated as a sustained ordelayed release dosage form to release the analgesic or the stoolsoftener over an extended time period following oral administration to ahuman patient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical dosage form for thesimultaneous administration of opiate analgesics and stool softeners.This allows the prescribing professional to direct the administration ofopiate analgesics or combinations containing opiates without having toassure patient compliance with a regimen of co-administered stoolsofteners. This also provides a method of adjusting the dose of stoolsoftener to match the patient's opiate ingestion without separateintervention by the prescriber or other health care professionals. Thisinclusion of a stool softener with an opiate also results in apharmaceutical composition having reduced potential for abuse anddiversion. Therefore, the present invention is directed topharmaceutical compositions comprising an analgesic or analgesiccombination and a stool softener.

The analgesic is typically an opiate, although combinations of opiatesor opiates in combination with another analgesic such as acetaminophenor aspirin are combined in a pharmaceutical composition containing astool softener. The analgesic includes at least one of morphine,meperidine, fentanyl, hydromorphone, oxymorphone, oxycodone,hydrocodone, methadone, propoxyphene, pentazocine, levorphanol orcodeine. In an alternative embodiment, the analgesic includes at leastone of morphine, meperidine, fentanyl, hydromorphone, oxymorphone,oxycodone, hydrocodone, methadone, propoxyphene, pentazocine,levorphanol, acetaminophen or combinations of these analgesics. Asacetaminophen has been shown to have a synergistic analgesic activitywith the opiate analgesics, the analgesic is preferably a combination ofan opiate or opiate derivative and acetaminophen. One particularlypreferred embodiment of the present invention is a pharmaceuticalcomposition comprising hydrocodone, acetaminophen and a stool softener.Another preferred embodiment of the present invention is apharmaceutical composition comprising oxycodone, acetaminophen and astool softener.

In the embodiments of the present invention comprising acetaminophen,the acetaminophen is present in a range of between about 10 mg and about2000 mg. Preferably, the acetaminophen is present in a range of about 50mg to about 1000 mg per dosage form. More preferably, the acetaminophenis present in a range of about 325 mg to about 750 mg per dosage form.Most preferably, each dosage form includes about 500 mg ofacetaminophen.

The amount of the opiate analgesic or analgesic combination contained inthe pharmaceutical composition depends upon the analgesic chosen andwhether the dosage form is to be formulated for immediate release orsustained release of the opiate or analgesic combination. For example,if morphine is the intended opiate, the morphine may be present in dosesbetween about 10 mg and about 60 mg including, but not limited to, about15 mg, about 20 mg, about 30 mg and about 40 mg. Alternatively, thepharmaceutical composition may be formulated to include between about 30mg to about 60 mg of morphine in a slow-release tablet or capsule. Ifmeperidine is chosen as the analgesic or a member of the analgesiccombination, the meperidine may be present in doses ranging from about50 mg to about 100 mg. If fentanyl is chosen as the analgesic or amember of the analgesic combination, the fentanyl may be present indoses equivalent to doses ranging from about 200 μg, to about 1600 μgincluding about 400 μg, about 600 μg, about 800 μg, about 1200 μg offentanyl base. If hydromorphone is chosen as the analgesic or a memberof the analgesic combination, the hydromorphone may be present in dosesranging from about 1 mg to about 5 mg of hydromorphone. If oxymorphoneis chosen as the analgesic or a member of the analgesic combination, theoxymorphone may be present in doses ranging from about 1 mg to about 10mg. If oxycodone is chosen as the analgesic or a member of the analgesiccombination, the oxycodone may be present in doses ranging from about 5mg to about 20 mg. If hydrocodone is chosen as the analgesic or a memberof the analgesic combination, the hydrocodone may be present in dosesranging from about 2.5 mg to about 15 mg, including, but not limited to,about 5 mg, about 7.5 mg and about 10 mg. If methadone is chosen as theanalgesic or a member of the analgesic combination, the methadone may bepresent in doses ranging from about 5 mg to about 10 mg. If propoxypheneis chosen as the analgesic or a member of the analgesic combination, thepropoxyphene may be present in doses ranging from about 32 mg to about65 mg of the hydrochloride salt or from about 50 mg to about 100 mg ofthe napsylate salt. If pentazocine is chosen as the analgesic or amember of the analgesic combination, the pentazocine may be present indoses including, but not limited to, about 50 mg pentazocine base ordoses of a pharmaceutically-acceptable salt of pentazocine approximatelyequivalent to about 50 mg of pentazocine base. If levorphanol is chosenas the analgesic or a member of the analgesic combination, thelevorphanol may be present in doses including but not limited to about 2mg of levorphanol tartrate. If codeine is chosen as the analgesic or amember of the analgesic combination, the codeine may be present in dosesincluding but not limited to doses of a pharmaceutically-acceptable saltof codeine approximately equivalent to a range from about 30 mg to about60 mg of codeine phosphate or approximately equivalent to a range ofabout 15 mg, to about 60 mg of codeine sulfate.

The stool softener may be any orally-administered medication that actsto increase any indicator of stool softener efficacy including stoolwater content, total stool output and bowel movement frequency.Preferably, the stool softener acts to increase the water content of thestool thereby softening the stool and making it easier to pass. Thestool softener is included in the pharmaceutical composition in a dosagethat is therapeutically effective in softening the stool in the intendedhuman or mammalian patient. The stool softener may be docusate,poloxamer 188, psyllium, methylcellulose, carboxymethyl cellulose,polycarbophil, bisacodyl, castor oil, magnesium citrate, magnesiumhydroxide, magnesium sulfate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium biphosphate or combinations of these compounds. Thepreferred stool softeners are psyllium and docusate.

In one embodiment of the present invention, the stool softener ispsyllium present in a range of between about 0.1 gram and about 10.0grams per dosage form. Preferably, the psyllium is present in a range ofabout 0.25 grams to about 2 grams per dosage form. More preferably, thepsyllium is present in a range of about 0.3 grams to about 0.75 gramsper dosage form. Most preferably, each dosage form includes about 0.5grams of psyllium. For example, in one preferred embodiment of thepresent invention, the pharmaceutical composition comprises codeinepresent as either about 30 mg or about 60 mg of codeine phosphate, about325 mg of acetaminophen and about 0.5 grams of psyllium.

In another embodiment of the present invention, the stool softener isdocusate present in the composition as any salt of dioctyl sodiumsulphosuccinate including the sodium and calcium salt. The term docusateis used herein to refer to dioctyl sodium sulphosuccinate and anypharmaceutically-acceptable salt thereof. In one embodiment of thepresent invention, the docusate is present in a range of between about10 mg and about 300 mg per dosage form. Preferably, the docusate ispresent in a range of about 25 mg to about 200 mg per dosage form. Morepreferably, the docusate is present in a range of about 50 mg to about100 mg per dosage form. Most preferably, each dosage form includes about50 mg of docusate. For example, in one preferred embodiment of thepresent invention, the pharmaceutical composition comprises codeinepresent as either about 30 mg or about 60 mg of codeine phosphate, about325 mg of acetaminophen and about 50 mg of docusate.

If poloxamer 188 is the intended stool softener, the poloxamer 188 ispreferably present in doses that range between about 100 mg and about400 mg including, but not limited to, about 200 mg. If methylcelluloseis chosen as the stool softener, the methylcellulose is preferablypresent in doses ranging from about 1 gram to about 6 grams. Ifcarboxymethylcellulose is chosen as the stool softener, thecarboxymethylcellulose is preferably present in doses ranging betweenabout 1 gram and about 6 grams. If polycarbophil is chosen as the stoolsoftener, the polycarbophil is preferably included in doses that rangefrom about 0.5 gram to about 6 grams. If bisacodyl is chosen as thestool softener, the bisacodyl is preferably included in doses rangingfrom about 5 mg to about 15 mg. If castor oil is chosen as the stoolsoftener, the castor oil is preferably included in doses ranging fromabout 1 ml to about 60 ml. If magnesium sulfate is chosen as the stoolsoftener, the magnesium sulfate is preferably included in doses rangingfrom about 2.5 grams to about 30 grams. If magnesium hydroxide is chosenas the stool softener, the magnesium hydroxide is preferably included indoses ranging from about 0.4 gram to about 4.8 grams. If magnesiumcitrate is chosen as the stool softener, the magnesium citrate ispreferably included in doses ranging from about 2.5 grams to about 18grams. If dibasic sodium phosphate is chosen as the stool softener, thedibasic sodium phosphate is preferably included in doses ranging fromabout 500 mg to about 3.8 grams. If monobasic sodium phosphate is chosenas the stool softener, the monobasic sodium phosphate is preferablyincluded in doses ranging from about 2.0 grams to about 17 grams. Ifsodium biphosphate is chosen as the stool softener, the sodiumbiphosphate is preferably included in doses ranging from about 2.5 gramsto about 20 grams.

When employed as pharmaceutical compositions, the analgesic and stoolsoftener combinations of the present invention are usually administeredorally. Compositions suitable for oral administration may be presentedas discrete units, such as capsules, tablets, lozenges, each containinga predetermined amount of the active compound. Other compositionsinclude suspensions in aqueous liquids or non-aqueous liquids such as asyrup, elixir or an emulsion. Such compositions are prepared in a mannerwell known in the pharmaceutical art and comprise at least one activecompound.

This invention also includes pharmaceutical compositions containing theanalgesic and stool softener active ingredients described aboveassociated with pharmaceutically-acceptable carriers. In making thecompositions of this invention, the active ingredients are usually mixedwith an excipient, diluted by an excipient or enclosed within such acarrier which can be in the form of a capsule, sachet, paper or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the pharmaceutical compositionsof the present invention can be in the form of oral solutions, syrups,soft and hard gelatin capsules and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activeingredients to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compounds are substantiallyinsoluble, they are ordinarily milled to a particle size of less than200 mesh. If an active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 10 mg to about 20 grams of activeingredients. The term “unit dosage form” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect in association witha suitable pharmaceutical excipient. Preferably, the analgesic compoundsand the stool softeners described above are typically employed at nomore than about 95 weight percent of the pharmaceutical composition,more preferably no more than about 75 weight percent, with the balancebeing pharmaceutically inert carrier(s).

The active compounds are effective over a wide dosage ranges and aregenerally administered in pharmaceutically effective amounts. It will beunderstood, however, that the amount of the compounds actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, theanalgesic to be administered, the age, weight, and response of theindividual patient, the severity of the patient's symptoms, and thelike.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredients are dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets or capsules. This solid preformulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, about 0.1 to about 20 grams of the active ingredientsof the present invention.

The tablets or capsules of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or capsule can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer which serves to resist disintegration in the stomachand permit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate as are known in the art. Thus, in oneembodiment of the present invention, the pharmaceutical dosage form isprepared such that upon administration, the analgesic or analgesiccombination is released from the dosage form for absorption while thestool softener is released in a slow, delayed or sustained-releasemanner. This may help to prevent diarrhea by slowing the exposure of thealimentary tract to the stool softener while simultaneously allowingsubstantially complete release and absorption of the painreliever-analgesic combinations. In this way the entire dose of stoolsoftener is released slowly over about 2 hours to about 12 hours.Preferably, the dosage is released over about 4 hours to about 8 hours.For example, in one preferred embodiment of the present invention, thepharmaceutical dosage form comprises hydrocodone and acetaminophenprepared for immediate release following administration and docusateformulated for sustained release over about 4 hours to about 12 hours orover about 4 hours to 24 hours.

In another embodiment of the present invention, the pharmaceuticalcomposition is formulated to release both the analgesic and the stoolsoftener in a sustained release manner. This is particularly effectivewhen the administration of a sustained release opiate or opiatecombination is desired in instances of chronic pain treatment. Forexample, one preferred embodiment of the present invention apharmaceutical composition formulated to contain oxycodone and docusatein a sustained release dosage form designed to release oxycodone anddocusate over about 4 hours to about 16 hours. More preferably, thisdosage form is designed to release the oxycodone and docusate over about8 hours to about 12 hours. In other specific embodiments, the analgesic,or stool softener, or both can be released between about 4 and 16 hours,or between about 8 and 24 hours.

The liquid forms in which the compositions of the present invention maybe incorporated for administration include aqueous solutions, suitablyflavored syrups, oil suspensions and flavored emulsions with edible oilssuch as cottonseed oil, sesame oil, coconut oil, or peanut oil as wellas elixirs and similar pharmaceutical vehicles.

Another embodiment of the present invention provides a method ofpreventing constipation in a patient receiving or in need of opiateanalgesic therapy by the co-administration of a stool softener with thechosen opiate. The method encompasses the oral administration of any oneof the pharmaceutical compositions of the present invention describedabove. The administration may continue for only a short time in the caseof an acute condition requiring opiate therapy or for long periods inthe case of conditions requiring chronic use of opiate analgesics. Thedosing is dependent upon the condition being treated, the patient'sindividual perception of pain and the use of the opiate on a set timeschedule as a prophylactic to prevent the onset of pain or on an asneeded basis in response to perceived pain. Ultimately however, theindividual dosing will be assessed by the prescribing professionalevaluating the patient, the condition treated, the analgesic to be used,diet and the expected duration of therapy. As noted in the Example 2below, the administration of opiates with a stool softener may increasesystemic absorption of the stool softener and slow absorption of theanalgesic. For this reason, the prescriber may recommend taking thecompositions of the present invention on an empty stomach or with fooddepending on the desired onset of the analgesic effect.

Additional objects, advantages, and novel features of this inventionwill become apparent to those skilled in the art upon examination of thefollowing examples thereof, which are not intended to be limiting.

EXAMPLES Example 1

This example provides pharmacokinetic bioavalability data for opiate andanalgesic medication orally administered in the presence of docusate anddemonstrates a minimal effect of coadministration of docusate on thebioavialability of the opiate and analgesic. The study is a comparative,randomized, single-dose, 4-way pilot crossover bioavailability study of500/10 mg acetaminophen/hydrocodone tablets and 50 mg docusate capsulesin healthy adults under fed and fasting conditions. The objective ofthis pilot study was to assess whether docusate is absorbed inmeasurable amounts, the effect of docusate on acetaminophen andhydrocodone pharmacokinetics and the effect of food on all analytes. Atotal of 12 subjects, 5 males and 7 females, were enrolled in the study,and 10 subjects, 4 males and 6 females, completed the study.

In each period, subjects were housed from at least 10 hours beforedosing until after the 12-hour draw. Subjects were required to fastovernight before dosing and for at least 4 hours thereafter. Subjectsrandomized to treatments C and D were in the fed state having started astandard breakfast 30 minutes prior to dosing. Subjects randomized toTreatments A and B were in a fasted state following a 10-hour overnightfast. Water was not permitted from 1 hour before until 1 hour afterdosing, but was allowed at all other times. Standard meals were providedat approximately 4 and 9 hours after dosing, and at appropriate timesthereafter. During housing, post-dose meal plans were identical for allperiods. Subjects underwent four separate treatments as follows:

Treatment A: Subjects received a single oral dose of one 10 mg/500 mgLortab® tablet and one 50 mg Colace® capsule taken with 240 mL of waterunder fasting conditions.

Treatment B: Subjects received a single oral dose of one 10 mg/500 mgLortab® tablet taken with 240 mL of water under fasting conditions.

Treatment C: Subjects received a single oral dose of one 10 mg/500 mgLortab® tablet and one 50 mg Colace® capsule taken with 240 mL of water30 minutes after the start of a standard breakfast.

Treatment D: Subjects received a single oral dose of one 10 mg/500 mgLortab® tablet taken with 240 mL of water 30 minutes after the start ofa standard breakfast. There was a seven-day washout interval betweeneach dose administration.

Blood samples were collected form each subject at the times listed inTable 1.

TABLE 1 Blood Sampling Schedule (hours) Analyte 0 0.25 0.5 0.67 0.83 11.33 1.66 2 3 4 6 8 12 Acetaminophen x x x X x x x x x x x x x xHydrocodone/ x x x x x x x x x x x x Hydromorphone Docusate x x x x x xx

Acetaminophen, hydrocodone and hydromorphone in plasma were analyzedusing validated LC/MS/MS methods. Docusate in plasma was analyzed usinga non-validated LC/MS/MS method. All samples were analyzed under non-GLPconditions. The analytical ranges were as follows: Acetaminophen:50.0–30000.0 ng/mL; Hydrocodone: 0.500–150.000 ng/mL; Hydromorphone:0.100–20.000 ng/mL; Docusate: 0.5–500 ng/mL. Docusate concentrationsabove the upper LOQ of 500 ng/mL correspond to extrapolated values. Dueto the low number of samples taken for docusate it was necessary toestimate the corresponding kel values with two points in most cases. TheAUC 0-t, AUCinf, AUC/AUCinf, Cmax, tmax, half-life and kelpharmacokinetic parameters were calculated for plasma acetaminophen,hydrocodone, hydromorphone and docusate. The results presented in Tables2 and 3 address whether docusate is absorbed in measurable amounts andthe effect of docusate on acetaminophen and hydrocodonepharmacokinetics. The effect of docusate on hydromorphonepharmacokinetics was also assessed.

The A/B comparisons in Tables 3 and 4 correspond to assessments underfasting conditions while the C/D comparisons correspond to assessmentsunder fed conditions.

TABLE 2 Least-Squares Ratio of 90% Confidence Analyses of Means (LSM)LSM Interval Variance (ANOVA) Form Form (A/B) (C/D) (A/B) (C/D)Parameters A Form B Form C D (%) (%) (%) (%) Acetaminophen in Plasma AUC0-t (ng · h/mL) 21007.48 20720.60 19652.06 19545.72 101.4 100.5 96.7–106.2 96.1–105.2 AUCinf (ng · h/mL) 22653.46 22004.82 21473.7721409.72 102.9 100.3  98.7–107.4 96.2–104.6 Cmax (ng/mL) 5452.4735924.279 3940.379 4023.527 92.0 97.9  80.2–105.7 85.8–111.8 Hydrocodonein Plasma AUC 0-t (ng · h/mL) 135.35 132.00 142.12 145.99 102.5 97.4 96.3–109.1 91.7–103.4 AUCinf (ng · h/mL) 162.06 151.17 170.22 174.74107.2 97.4 100.0–114.9 91.4–103.8 Cmax (ng/mL) 24.28794 24.2438422.26302 22.94215 100.2 97.0  89.5–112.1 87.1–108.1

TABLE 3 Analyses of Least-Squares Ratio of 90% Confidence Variance(ANOVA) Means (LSM) LSM Interval Parameters Form A Form B Form C Form D(A/B) % (C/D) % (A/B) % (C/D) % Hydromorphone in Plasma AUC 0-t (ng ·h/mL) 6.5433 7.1075 6.3270 6.2051 92.1 102.0 85.0–99.7 94.5–110.0 AUCinf(ng · h/mL) 10.2390 10.9436 10.9046 10.9575 93.6 99.5 84.4–103.889.2–111.0 Cmax (ng/mL) 0.96508 0.99512 0.74228 0.74216 97.0 100.086.8–108.3 90.0–111.2 Docusate in Plasma AUC 0-t (ng · h/mL) 1171.94 N/A1455.68 N/A N/A N/A N/A N/A AUCinf (ng · h/mL) 1171.31 N/A 1508.26 N/AN/A N/A N/A N/A Cmax (ng/mL) 608.14244 N/A 634.74354 N/A N/A N/A N/A N/A

Measurable docusate concentrations were observed throughout the periodof blood sampling. Hence, it may be concluded that docusate is absorbedin measurable amounts. Correspondingly, it was possible to calculatepharmacokinetic parameters for docusate. It should be noted, however,that the pharmacokinetic parameters have not been robustly assessed asthere were only 7 samples collected for docusate analysis.

To assess the effect of docusate on the pharmacokinetics ofacetaminophen, hydrocodone and hydromorphone, ratios of least squaresmeans and 90% confidence intervals for the difference between drugformulation LSMs were derived from the analyses on the ln-transformedpharmacokinetic parameters AUC 0-t, AUCinf and Cmax. The comparisons ofinterest were A versus B (fasted conditions) and C versus D (fedconditions). For all analytes under both fasted and fed conditions, theratios of least squares means and corresponding 90% confidence intervalsfall within the range of 80–125%. It should also be noted that docusatehas the effect of delaying tmax by approximately 30 minutes for allanalytes under both fasted and fed conditions. However, from theseresults it is concluded that docusate has no significant effect on thepharmacokinetics of acetaminophen, hydrocodone or hydromorphone underfed and fasted conditions.

Example 2

This example demonstrates the affect of food on the pharmacokinetics ofacetaminophen, hydrocodone, hydromorphone and docusate in subjects underthe clinical conditions described in Example 1. In Table 4 and Table 5,the C/A comparisons correspond to assessments for docusateco-administered with acetaminophen and hydrocodone (Lortab®+Colace®)while the D/B comparisons correspond to assessments for acetaminophenand hydrocodone (Lortab®) administered alone.

TABLE 4 Analyses of Least-Squares Ratio of 90% Confidence Variance(ANOVA) Means (LSM) LSM Interval Parameters Form A Form B Form C Form D(C/A) % (D/B) % (C/A) % (D/B) % Acetaminophen in Plasma AUC 0-t (ng ·h/mL) 21007.48 20720.60 19652.06 19545.72 93.5 94.3 89.3–98.0  90.2–98.7AUCinf(ng · h/mL) 22653.46 22004.82 21473.77 21409.72 94.8 97.390.7–99.0  93.5–101.3 Cmax (ng/mL) 5452.473 5924.279 3940.379 4023.52772.3 67.9 62.9–83.0  59.5–77.5 Hydrocodone in Plasma AUC 0-t (ng · h/mL)135.35 132.00 142.12 145.99 105.0 110.6 98.6–111.8 104.2–117.4 AUCinf(ng · h/mL) 162.06 151.17 170.22 174.74 105.0 115.6 98.0–112.6108.5–123.2 Cmax (ng/mL) 24.28794 24.24384 22.26302 22.94215 91.7 94.681.9–102.6  85.0–105.4

TABLE 5 Analyses of Least-Squares Ratio of 90% Confidence Variance(ANOVA) Means (LSM) LSM Interval Parameters Form A Form B Form C Form D(C/A) % (D/B) % (C/A) % (D/B) % Hydromorphone in Plasma AUC 0-t (ng ·h/mL) 6.5433 7.1075 6.3270 6.2051 96.7 87.3  89.3–104.7 80.9–94.2 AUCinf(ng · h/mL) 10.2390 10.9436 10.9046 10.9575 106.5 100.1  95.3–119.190.6–110.6 Cmax (ng/mL) 0.96508 0.99512 0.74228 0.74216 76.9 74.6 68.9–85.9 67.1–82.9 Docusate in Plasma AUC 0-t (ng · h/mL) 1171.94 N/A1455.68 N/A 124.2 N/A 112.8–136.8 N/A AUCinf (ng · h/mL) 1171.31 N/A1508.26 N/A 128.8 N/A 109.1–151.9 N/A Cmax (ng/mL) 608.14244 N/A634.74354 N/A 104.4 N/A  72.4–150.4 N/A

Ratios of least squares means and 90% confidence intervals for thedifference between drug formulation LSMs were derived from the analyseson the ln-transformed pharmacokinetic parameters AUC 0-t, AUCinf andCmax. The comparisons of interest were C versus A (Lortab® and Colace®co-administered) and D versus B (Lortab® administered alone).

For acetaminophen and hydromorphone, the ratio of least-squares meansand 90% confidence intervals derived from the analysis of theln-transformed parameters AUC 0-t and AUCinf were within the 80–125%range for both the C versus A and D versus B comparisons. However, thecorresponding ratios of least-squares means and 90% confidence intervalsfor the In-transformed Cmax parameter were not within this range. Inaddition, it is apparent that food delays the tmax by approximately 1hour for acetaminophen and by approximately 2 hours for hydromorphone.Based on these results, it may be concluded that food has the effect oflowering the Cmax and delaying tmax for both acetaminophen andhydromorphone but does not affect the extent of exposure, as measured bythe AUC parameters.

For hydrocodone, the ratio of least-squares means and 90% confidenceintervals derived from the analysis of the ln-transformed parameters AUC0-t, AUCinf and Cmax were within the 80–125% range for both the C versusA and D versus B comparisons. In addition, food appears to delay tmaxfor hydrocodone by approximately 1 hour. It should be noted that in theD versus B comparison (Lortab® administered alone), the analysis of theln-transformed AUCinf parameter yielded a ratio of least squares meansof 115.6%. This suggests that food tends to slightly increase the extentof exposure of hydrocodone. Nevertheless, it may be generally concludedthat food has no significant effect on the rate (Cmax) or the extent(AUC) of exposure of hydrocodone.

For docusate, the ratio of least-squares means derived from the analysisof the ln-transformed parameters AUC 0-t and Cmax are within the 80–125%range while the corresponding 90% confidence intervals were not withinthis range. In the case of the analysis of the ln-transformed parameterAUCinf for docusate, the ratio of least-squares means and 90% confidenceinterval were not within the 80–125% range. In addition, food appears todelay tmax for docusate by approximately 30 minutes. Based on theseresults it may be concluded that food tends to increase the extent ofexposure (AUC) of docusate. In the case of Cmax, while it is noted thatthe 90% confidence interval is not within the 80–125% range, the ratioof least-squares means of 104.5% may suggest that the rate of exposureof docusate is not significantly affected by food.

The foregoing discussion of the invention has been presented forpurposes of illustration and description. The foregoing is not intendedto limit the invention to the form or forms disclosed herein. Althoughthe description of the invention has included description of one or moreembodiments and certain variations and modifications, other variationsand modifications are within the scope of the invention, e.g., as may bewithin the skill and knowledge of those in the art, after understandingthe present disclosure. It is intended to obtain rights which includealternative embodiments to the extent permitted, including alternate,interchangeable and/or equivalent structures, functions, ranges or stepsto those claimed, whether or not such alternate, interchangeable and/orequivalent structures, functions, ranges or steps are disclosed herein,and without intending to publicly dedicate any patentable subjectmatter.

1. A mono-phasic pharmaceutical composition suitable for single doseadministration for reducing the risk of constipation caused by theadministration of an opioid analgesic consisting of: about 2.5 mg/doseto about 15 mg/dose of hydrocodone; about 10 mg/dose to about 2000mg/dose of acetaminophen; a stool softener selected from the groupconsisting of about 50 mg/dose to about 100 mg/dose of docusate andabout 100 mg/dose to about 400 mg/dose of poloxamer 188; and, apharmaceutically acceptable carrier.
 2. The pharmaceutical compositionof claim 1, wherein the acetaminophen is present in about 50 mg/dose toabout 1000 mg/dose of acetaminophen and the stool softener is present inabout 50 mg/dose to about 100 mg/dose of docusate.
 3. The pharmaceuticalcomposition of claim 1, wherein the acetaminophen is present in about325 mg/dose to about 750 mg/dose of acetaminophen and the stool softeneris present in about 50 mg/dose to about 100 mg/dose of docusate.
 4. Thepharmaceutical composition of claim 3, wherein the composition containsabout 325 mg/dose of acetaminophen and about 50 mg/dose of docusate. 5.The pharmaceutical composition of claim 3, wherein the compositioncontains about 325 mg/dose of acetaminophen and about 100 mg/dose ofdocusate.
 6. The pharmaceutical composition of claim 1, wherein theacetaminophen is present in about 50 mg/dose to about 1000 mg/dose ofacetaminophen and the stool softener is present in about 100 mg/dose toabout 400 mg/dose of poloxamer
 188. 7. The pharmaceutical composition ofclaim 1, wherein the composition contains about 325 mg/dose to about 750mg/dose of acetaminophen and the stool softener is present in about 100mg/dose to about 400 mg/dose of poloxamer
 188. 8. The pharmaceuticalcomposition of claim 7, wherein the composition contains about 325mg/dose of acetaminophen and about 200 mg/dose of poloxamer 188.